Treatment of crohn&#39;s disease with laquinimod

ABSTRACT

This application provides for a method of treating a subject suffering from Crohn&#39;s disease, the method comprising periodically administering to the subject an amount of laquinimod or pharmaceutically acceptable salt thereof effective to treat the subject. This application provides for use of laquinimod in the manufacture of a medicament for treating a subject suffering from Crohn&#39;s disease. This application also provides for a pharmaceutical composition comprising laquinimod for use in treating a subject suffering from Crohn&#39;s disease.

This application claims the benefit of U.S. Provisional Application No.61/273,167, filed Jul. 30, 2009, the entire content of which is herebyincorporated by reference herein.

Throughout this application various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

BACKGROUND

Crohn's disease (CD) and Ulcerative Colitis (UC) are the two major typesof Inflammatory Bowel Disease (IBD)—a generic classification for a groupof nonspecific, idiopathic inflammatory disorders of, thegastrointestinal (GI) tract which also includes Indeterminate Colitis(IC). Indeterminate Colitis refers to the up to 15% of IBD cases wheredistinguishing between CD and UC is impossible. (Kasper, 2008) Both CDand UC tend to be chronic in nature and run a course characterized byexacerbations and remissions.

CD may occur in any part of the GI tract, but most commonly affects thedistal ileum and colon. It is characterized by transmural inflammationof the gastrointestinal wall, interspersed with “skip” areas of normaltissue, leading to the characteristic endoscopic and radiographicappearance of the disease. In about half the cases, biopsy specimensreveal the pathognomonic histology of noncaseating granulomas (Friedman,2001).

Although CD usually presents as acute or chronic bowel inflammation, theinflammatory process evolves toward one or two patterns of disease: afibrostenotic-obstructing pattern or a penetrating-fistulous pattern,each with different treatments and prognoses (Friedman, 2001).

The characteristic inflammatory presentation of Crohn's disease is ofabdominal pain, diarrhea, fever and weight loss which may be complicatedby intestinal fistulization, obstruction, or both. Fistula formation mayoccur to the adjacent bowel, the skin, the urinary bladder, or otherlocations. Obstruction, if present, is initially intermittent due tobowel wall edema and spasm; further progression may lead to chronicscarring and stricture formation. Perianal disease is common and maymanifest as anal fissure, perianal fistula, or abscess (Friedman, 2001;Wu, 2007).

Extra-intestinal manifestations may also occur and include jointinflammation (e.g., peripheral arthritis, ankylosing spondylitis), skinlesions (e.g., erythema nodosum, pyoderma gangrenosum), ocularinvolvement (e.g., iritis, uveitis) and liver disorders (e.g., hepaticsteatosis, primary sclerosing cholanitis) (Friedman, 2001; Wu, 2007).

The incidence of CD varies within different geographic areas. Northerncountries such as the US, UK, Norway and Sweden have the highest rates.The incidence of CD in the US is approximately 7 per 100,000. Countriesin southern Europe, South Africa and Australia have lower incidencerates of 0.9 to 3.1 per 100,000. The disease is rare in Asia and SouthAmerica (Friedman, 2001).

The peak age of onset of Crohn's disease occurs between the ages of 15and 30 years, with a second peak of occurrence between the ages of 60-80years (Friedman, 2001).

The fundamental cause of CD is unknown. There are four basic factorsaffecting the pathophysiology of CD: genetics, immune dysregulation,epithelial barrier dysfunction and the constitution of microbial flora.Evidence suggests that genetic predisposition leads to an unregulatedintestinal immune response to an environmental, dietary or infectiousagent (Friedman, 2001; Wen, 2004). A number of studies suggest that CDis a T-helper 1 (Th-1) mediated disease and that the excessive Th1-cellactivity leading to the production of a wide range of proinflammatorycytokines [including interleukin (IL)-1, IL-2 and tumor necrosis factor(TNF)-α] and an imbalance between proinflammatory and anti-inflammatoryreactivity, is a critical component of CD (Hendrickson, 2002). However,no inciting antigen has been identified.

In the absence of a key diagnostic test, the diagnosis of Crohn'sdisease is based on endoscopic, radiographic and pathological findingsdocumenting focal, asymmetric transmural or granulomatous features.Laboratory abnormalities include non-specific markers of inflammationsuch as elevated sedimentation rate and C-reactive protein (CRP). Inmore severe cases, finding may include hypoalbuminemia, anemia, andleukocytosis (Friedman, 2001; Wu, 2007).

There is no definitive treatment or cure for CD. The major therapeuticgoals are the reduction of signs and symptoms, induction and maintenanceof remission and most importantly, the prevention of disease progressionand complications.

Sulfasalazine and other 5-aminosalicylic acid agents, antibiotics suchas metronidazole and ciprofloxacin, corticosteroids, immunosupressorssuch as azathioprine and 6-mercaptopurine and biologic agents such asanti-TNFα agents and anti-integrins, that prevents leukocyteinfiltration have shown to be useful in the induction of remissionand/or in its maintenance (Targan, 1977; Hanauer, 2002; Colombel, 2007;Ghosh, 2003; Sandborn, 2005; Schreiber, 2005; Schreiber, 2007; Kozuch,2008). Many of these medicinal products, however, are only moderateefficacious and are associated with challenging side effects (Hommes,2003; Thomas, 2004; Colombel, 2004; Van Assche, 2005; Vermeire, 2003;Sweetman, 2006). In addition, the newer biologic agents have arelatively inconvenient parenteral route of administration. There is,therefore, a definite need for alternative therapies with betterrisk-benefit profiles and a more convenient route of administration thanthe currently available options.

Disclosed is a method of treating Crohn's disease using laquinimod.Laquinimod is a novel synthetic compound with high oral bioavailability,which has been suggested as an oral formulation for Relapsing RemittingMultiple Sclerosis (MS). Laquinimod and its sodium salt form aredescribed, for example, in U.S. Pat. No. 6,077,851. The effects oflaquinimod on Crohn's disease have not been reported.

SUMMARY OF THE INVENTION

This application provides for a method of treating a subject sufferingfrom Crohn's disease, the method comprising periodically administeringto the subject an amount of laquinimod or pharmaceutically acceptablesalt thereof effective to treat the subject.

This application provides for use of laquinimod in the manufacture of amedicament for treating a subject suffering from Crohn's disease.

This application also provides for a pharmaceutical compositioncomprising laquinimod for use in treating a subject suffering fromCrohn's disease.

DETAILED DESCRIPTION OF THE INVENTION

This application provides for a method of treating a subject sufferingfrom Crohn's disease, the method comprising periodically administeringto the subject an amount of laquinimod or pharmaceutically acceptablesalt thereof effective to treat the subject.

In one embodiment, the amount of laquinimod is effective to reduce asymptom of Crohn's disease in the subject, induce clinical response,induce or maintain clinical remission, inhibit disease progression, orinhibit a disease complication in the subject.

In another embodiment, the amount of laquinimod is effective to reducethe Crohn's Disease Activity Index score of the subject, lower theC-Reactive Protein level of the subject, lower the fecal calproteinlevel of the subject, or reduce the number of open draining fistulas inthe subject.

In one embodiment, the amount of laquinimod is effective to lower thesubject's dependence on steroids.

In one embodiment, the Crohn's Disease Activity Index score of thesubject is reduced by at least 100 points. In another embodiment, theCrohn's Disease Activity Index score of the subject is reduced to under150.

In one embodiment, the number of open draining fistulas in the subjectis decreased at least 50% as compared to prior to initiation of theperiodic administration.

In one embodiment, the periodic administration is oral.

In one embodiment, the amount is administered by a unit dose of 0.5 mgof laquinimod. In another embodiment, the periodic administration isdaily administration. In another embodiment, the amount of laquinimod is0.5-2.0 mg/day. In another embodiment, the amount of laquinimod is 1.0mg/day. In another embodiment, the amount of laquinimod is 1.5 mg/day.In yet another embodiment, the amount of laquinimod is 2.0 mg/day.

In one embodiment, a loading dose of an amount different from theintended dose is administered for a period of time at the start of theperiodic administration. In another embodiment, a loading dose of doublethe amount of the intended dose is administered for a period of time atthe start of the periodic administration. In another embodiment, aloading dose of an amount different from the intended dose isadministered for two days at the start of the periodic administration.In yet another embodiment, a loading dose of double the amount of theintended dose is administered for two days at the start of the periodicadministration.

In one embodiment, the subject had active moderate to severe Crohn'sdisease prior to the administration of laquinimod. In anotherembodiment, the subject had a Crohn's Disease Activity Index score of220-450 prior to the administration of laquinimod. In anotherembodiment, the subject had a C-Reactive Protein level of above 5 mg/Lprior to the administration of laquinimod. In another embodiment,diagnosis of the subject prior to administration excluded IndeterminateColitis. In yet another embodiment, diagnosis of the subject prior toadministration excluded Ulcerative Colitis.

In one embodiment, the periodic administration continues for 8 weeks ormore.

In one embodiment, the laquinimod is in the form of laquinimod sodium.

In one embodiment, the subject is a human.

In one embodiment, the method further comprises administration of5-aminosalicylic acid, antibiotics, corticosteroids, immunosuppressors,or biologic agents including TNFα agents and anti-integrins.

This application also provides for use of laquinimod in the manufactureof a medicament for treating a subject suffering from Crohn's disease.

This application also provides for a pharmaceutical compositioncomprising laquinimod for use in treating a subject suffering fromCrohn's disease.

All combinations of the various elements described herein are within thescope of the invention.

A pharmaceutically acceptable salt of laquinimod as used in thisapplication includes lithium, sodium, potassium, magnesium, calcium,manganese, copper, zinc, aluminum and iron. Salt formulations oflaquinimod and the process for preparing the same are described, e.g.,in U.S. Patent Application Publication No. 2005/0192315 and PCTInternational Application Publication No. WO 2005/074899, each of whichis hereby incorporated by reference into this application.

A dosage unit may comprise a single compound or mixtures of compoundsthereof. A dosage unit can be prepared for oral dosage forms, such astablets, capsules, pills, powders, and granules.

Laquinimod can be administered in admixture with suitable pharmaceuticaldiluents, extenders, excipients, or carriers (collectively referred toherein as a pharmaceutically acceptable carrier) suitably selected withrespect to the intended form of administration and as consistent withconventional pharmaceutical practices. The unit will be in a formsuitable for oral administration. Laquinimod can be administered alonebut is generally mixed with a pharmaceutically acceptable carrier, andco-administered in the form of a tablet or capsule, liposome, or as anagglomerated powder. Examples of suitable solid carriers includelactose, sucrose, gelatin and agar. Capsule or tablets can be easilyformulated and can be made easy to swallow or chew; other solid formsinclude granules, and bulk powders. Tablets may contain suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents flow-inducing agents, and melting agents.

Specific examples of the techniques, pharmaceutically acceptablecarriers and excipients that may be used to formulate oral dosage formsof the present invention are described, e.g., in U.S. Patent ApplicationPublication No. 2005/0192315, PCT International Application PublicationNos. WO 2005/074899, WO 2007/047863, and WO/2007/146248, each of whichis hereby incorporated by reference into this application.

General techniques and compositions for making dosage forms useful inthe present invention are described-in the following references: 7Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors,1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981);Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.). These references in their entireties are herebyincorporated by reference into this application.

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, and meltingagents. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,dicalcium phosphate, calcium sulfate, mannitol, sorbitol,microcrystalline cellulose and the like. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornstarch, natural and synthetic gums such as acacia, tragacanth, or sodiumalginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes,and the like. Lubricants used in these dosage forms include sodiumoleate, sodium stearate, sodium benzoate, sodium acetate, sodiumchloride, stearic acid, sodium stearyl fumarate, talc and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, croscarmellose sodium, sodium starchglycolate and the like.

Terms

As used herein, and unless stated otherwise, each of the following termsshall have the definition set forth below.

An “amount” or “dose” of laquinimod as measured in milligrams refers tothe milligrams of laquinimod acid present in a preparation, regardlessof the form of the preparation.

As used herein, a “loading dose” refers to an initial higher dose of adrug that may be given at the beginning of a course of treatment beforedropping down to a lower “intended dose” or “maintenance dose”.

As used herein, “Crohn's Disease Activity Index” or “CDAI” is a researchtool developed by W R Best and colleagues from the Midwest RegionalHealth Center in Illinois, in 1976 (Best, 1976) to quantify the symptomsof patients with Crohn's disease. The index is the most widely usedinstrument for evaluation of Crohn's disease activity (Best, 1976; Best,1979; Sandborn, 2002) and consists of eight factors/variables.

The eight variables are summed after adjustment with a weighting factor.The components of the CDAI and weighting factors are shown in thefollowing table:

Weighting Clinical or laboratory variable factor Number of liquid orsoft stools (sum of each day for 7 days) x2 Abdominal pain (graded from0-3 on severity) (sum of each x5 day for 7 days) General well being,subjectively assessed from 0 (well) to 4 x7 (terrible) (sum of each dayfor 7 days) Presence of Crohn's disease complications x20 Use ofdyphenoxylate or loperamide for diarrhea during the x30 past week (0 =no, 1 = yes) Presence of an abdominal mass (0 as none, 2 asquestionable, x10 5 as definite) Absolute deviation of Hematocrit from47% in men and 42% x6 in women Percentage deviation from standard weightx1

The first 4 of these variables and the presence of fever above 37.8° C.,are self-reported in subject diaries, the remaining 4 are assessed atthe study visit. Height and standard weight assessment are based onstandard height-weight tables.

Total CDAI scores range from 0 to approximately 600 where the higher thescore, the more active the disease. A CDAI score of less than 150 pointsdenotes “clinical remission” of the Crohn's disease, of between 150 to219 points denotes “active mild Crohn's disease”, of between 220 to 450points denotes “active moderate Crohn's disease” and of more than 450points denotes “active severe Crohn's disease”.

“Clinical response” means that the subject's Crohn's disease symptomshave decreased in severity and/or in number. “Clinical remission” meansthat the subject's Crohn's disease symptoms have decreased in severityand/or in number to below a defined level, e.g., below 150 points on theCDAI scale. “Clinical remission” and “clinical response” may be measuredin accordance with the EMEA draft guidelines on the development of newmedicinal products for the treatment of Crohn's disease. The EMEAguidelines define “clinical remission” as reduction in CDAI score to atotal score below 150 points and “clinical response” as if remission hasbeen achieved or a reduction of at least 100 points in the total CDAIscore has been observed, compared to baseline at the end of thetreatment period (EMEA, 2007).

“Indeterminate Colitis” or “IC” is used clinically in patients with someform of Inflammatory Bowel Disease in whom a definite diagnosis ofeither Ulcerative Colitis (UC) or Crohn's Disease (CD) has not beenmade, either on colonoscopy or colonic biopsy before colectomy. Althoughsome patients diagnosed with Indeterminate Colitis go on to develop UCor CD, studies have shown that over a median follow up period of 10years, many patients retain diagnosis of Indeterminate Colitis. (Guindi,2004)

“Inhibition” of disease progression or disease complication in a subjectmeans preventing or reducing the disease progression and/or diseasecomplication in the subject.

As used herein, “C-reactive protein” or “CRP” is an inflammatorymediator whose levels are raised under conditions of acute inflammatoryrecurrence and rapidly normalize once the inflammation subsides. Crohn'sdisease may be characterized according to disease behavior:predominantly nonstricturing nonpenetrating (inflammatory), stricturingor penetrating (Silverberg, 2005). The origin of symptoms such asdiarrhea, fatigue, or abdominal pain (affects the CDAI score) may bemultifactorial and does not necessarily correlate with the existence ofprominent inflammatory lesions of the gastrointestinal (GI) tract.Predominantly nonstricturing nonpenetrating (inflammatory) Crohn'sdisease may be characterized by high CRP levels. Therefore the CRP mayserve as a surrogate marker to monitor inflammatory disease activity andresponse to treatment (Solem, 2005; Denis, 2007; Chamouard, 2006).

As used herein, “calprotectin” is a calcium and zinc bindinganti-microbial protein released by granulocytes. This protein can bedetected in stool and its concentration reflects the number ofpolymorphonuclear leukocytes (PMN), migrating into the gut lumen. It istherefore considered a bio-marker for intestinal inflammation.

As used herein, “effective” when referring to an amount of laquinimodrefers to the quantity of a laquinimod that is sufficient to yield adesired therapeutic response without undue adverse side effects (such astoxicity, irritation, or allergic response) commensurate with areasonable benefit/risk ratio when used in the manner of this invention.

As used herein, “treating” encompasses, e.g., inducing inhibition,regression, or stasis of the disorder.

As used herein, “pharmaceutically acceptable carrier” refers to acarrier or excipient that is suitable for use with humans and/or animalswithout undue adverse side effects (such as toxicity, irritation, andallergic response) commensurate with a reasonable benefit/risk ratio. Itcan be a pharmaceutically acceptable solvent, suspending agent orvehicle, for delivering the instant compounds to the subject.

It is understood that where a parameter range is provided, all integerswithin that range, and tenths thereof, are also provided by theinvention. For example, “5-10%” includes 5.0%, 5.1%, 5.2%, 5.3%, 5.4%etc. up to 10.0%.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

EXPERIMENTAL DETAILS Example 1: Clinical Trial (Phase IIa)—Assessment ofOral Laquinimod in Active Moderate to Severe Crohn's Disease

A phase IIa, multicenter, randomized, double-blind, placebo-controlled,sequential cohorts, dose range finding study is conducted to evaluateescalating doses of Laquinimod in active moderate to severe Crohn'sdisease.

Study Title

A Phase IIa, Multicenter, Randomized, Double-Blind, Placebo-Controlled,Sequential Cohorts, Dose Range Finding Study to Evaluate the Safety,Tolerability and Clinical Effect of Escalating Doses of Laquinimod inActive Moderate to Severe Crohn's disease.

Participating Countries and Number of Sites

Europe (Belgium, France, Italy, Netherlands, Spain, Poland and UK),Israel and South Africa in approximately 50 sites.

Number of Subjects

There are 4 distinct sequential cohorts with approximately 45 subjectsfor each of the cohorts, randomized in a 2:1 ratio (˜30 subjects onlaquinimod and ˜15 on placebo). Overall up to ˜180 Crohn's diseasepatients are enrolled.

Investigational Medicinal Product (IMP) & Dosage

One or more capsules containing laquinimod 0.5 mg or matching placeboare administered orally once daily:

1^(st) cohort—laquinimod 0.5 mg (1×0.5) or matching placebo;

2^(nd) cohort—laquinimod 1.0 mg (2×0.5) or matching placebo;

3^(rd) cohort—laquinimod 1.5 mg (3×0.5) or matching placebo; and

4^(th) cohort—laquinimod 2.0 mg (4×0.5) or matching placebo.

The 0.5 mg laquinimod capsules were prepared using 0.534 mg oflaquinimod sodium per capsule (which is equivalent to 0.5 mg oflaquinimod acid). The capsules were prepared using a blend proportionalto the 0.6 mg capsules described in PCT International Application No.PCT/US2007/013721 (WO 2007/146248). The capsules were prepared accordingto the method described in PCT International Application No.PCT/US2007/013721 (WO 2007/146248), which is hereby incorporated byreference into this application.

A loading dose regimen of double the maintenance/intended dose is givenduring the first two days of study drug treatment. Thereafter, startingon day 3, the daily maintenance/intended dose is administered.

Table 1 summarizes the number of capsules and total dose which areadministered daily for each of the 4 study cohorts, at different timepoints throughout the treatment period. “BID” indicates that the dose isadministered twice daily. “QD” indicates that the dose is administeredonce daily.

TABLE 1 Day 1 Day 2 Day 3 onwards 0.5 mg/plc 0.5 mg/plc 0.5 mg/plcCohort capsules/day Dose/day capsules/day Dose/day capsules/day Dose/day1 1 + 1 (BID) 1 mg/placebo 1 + 1 (BID) 1 mg/placebo 1 (QD) 0.5 mg/placeo2 2 + 2 (BID) 2 mg/placebo 2 + 2 (BID) 2 mg/placebo 2 (QD)   1 mg/placeo3 3 + 3 (BID) 3 mg/placebo 3 + 3 (BID) 3 mg/placebo 3 (QD) 1.5 mg/placeo4 4 + 4 (BID) 4 mg/placebo 4 + 4 (BID) 4 mg/placebo 4 (QD)   2 mg/placeo

Subjects are required to maintain CDAI diary cards for each day of thescreening period and, if randomized, on each day of the treatment andfollow-up period. The scores obtained from the seven consecutive diariescompleted prior to the baseline visit and to each of weeks 1, 2, 4, 6, 8and 12 contribute to a total CDAI score at each of the time points.

Allowed previous standard of care treatment is kept stable throughoutthe study (including the follow-up period, as defined herein).

Study Duration Each Cohort (Dose Group) is Evaluated for Up to 14 Weeks

Screening: between 1-2 weeks

Treatment period: 8 weeks

Follow-up period: 4 weeks

Study Population

Moderate to severe Crohn's disease (CD) subjects as determined by aCrohn's Disease Activity Index (CDAI) score of 220-450 (inclusive).

Study Design

This Phase IIa, randomized, double-blind, placebo-controlled, sequentialcohorts, dose range finding study to assess the safety tolerability andclinical effect of escalating dose of laquinimod in active moderate tosevere Crohn's disease is the first study to assess the safety,tolerability and efficacy of laquinimod in active CD subjects.

This study investigates laquinimod doses at 0.5, 1.0, 1.5 and 2.0 mgdaily. Each dose is studied sequentially in a distinct cohort.

Subjects are assessed for study eligibility 1 to 2 weeks prior tobaseline.

Approximately 45 eligible subjects are assigned to each cohort. Subjectsare randomized in a 2:1 ratio for either of the following treatmentarms:

1. Oral laquinimod (˜30 subjects).

2. Matching oral placebo (˜15 subjects).

Each successive cohort is screened/randomized only when the twoconditions below have been met:

-   1. Randomization of at least 45 subjects for the preceding cohort    and closure of screening and randomization of the preceding cohort.-   2. Decision of a safety committee to proceed to the next dose level.

This decision is based on data review of at least 15 subjects who havecompleted at least 4 weeks of treatment in the preceding cohort, as wellas all other data obtained in the study for any of the precedingcohorts.

All study investigators are informed when screening and/or randomizationare closed for the preceding cohort and opened for the next cohort/doselevel. All subjects in screening phase are allowed to be randomized (ifeligible) to the preceding cohort or the next cohort, whichever isopened at randomization/baseline visit.

The safety committee may determine at any of these safety evaluations,that a Dose Limiting Toxicity (DLT) has been reached. Criteria for DLTare not predefined and are based solely on the safety committee's bestmedical judgment.

In case a dose limiting toxicity has been reached the following decisionoptions exist for the safety committee:

-   1. Complete the current cohort without proceeding to the next dose    level/cohort; and-   2. Terminate the study immediately.

Scheduled in-clinic visits are conducted at screening, baseline and atweeks 1, 2, 4, 6 and 8. Treatment with laquinimod/placebo arediscontinued on visit week 8 and a follow-up/study completion visit isconducted at week 12. Subjects who early-discontinues study drug priorto visit week 8 go to follow-up termination visit within 4 weeks (28days) of study drug discontinuation.

Unscheduled visits for safety or for any other reason may be conductedat any time during the study.

During the study period the CDAI score is assessed in addition toroutine safety laboratory tests and PK analysis.

Based on previous pharmacokinetic studies, laquinimod reaches steadystate following approximately 10-12 days of daily maintenance dosing. Inorder to decrease the time to steady state and potentially decrease timeto response, a loading dose regimen described below is used to allowsteady state levels to be reached in approximately 6-7 days.

A loading dose regimen of the study drug is given during the first twodays of treatment (day 1/baseline and thereafter). The first loadingdose of the study is administered at the site. The loading dose isdouble the intended dose for the first two days and is administeredtwice daily (BID) with 12 hour interval between dosing. Thereafter,starting on day 3, the dosing regimen consists of the intended dose oncedaily (QD) (see Table 1):

-   1. Day 1 (Baseline): loading dose of the drug (intended dose at 0    hour, at the site and intended dose at 12 hours). Total dose is    twice the intended dose.-   2. Day 2: loading dose of the study drug (intended dose at 0 hour    and intended dose at 12 hours). Total dose is twice the intended    dose.-   3. Day 3: Intended/maintenance dose of the study drug.

Allowed previous standard of care treatment is kept stable throughoutthe study (including the follow-up period as defined herein).

PK Analysis Pharmacokinetic Sub-Study (PK)—Ancillary Study Performed inSubset of Sites

Blood samples for PK analysis—24 h profile—are collected from subjectsin the first cohort (0.5 mg/placebo) on week 4.

A single, pre-dose sample is collected from the first cohort (0.5mg/placebo) on week 1 as part of steady state course assessment.

Population PK Study (PPK)

Blood samples for PPK evaluation are collected at weeks 2 and 8 from allsubjects in all cohorts. A pre-dose sample and a single sample atpost-dose time range within 0.5 to 6 hours are collected.

Pharmacogenetic Sub-Study

Blood samples for the pharmacogenetic sub-study are collected from allsubjects who sign the separate informed consent form and upon EthicsCommittee (EC) approval.

Allowed Concomitant Medications During Study

In general the dose of allowed concomitant medication is kept stablethroughout the study (including the follow-up period). Any newmedication/treatment for CD or dose increase not allowed by theprotocol, throughout the study treatment period, results in majorprotocol violation and are regarded as a treatment failure. Decrease indose or dose regiment, not allowed by the protocol, also results inmajor protocol violation.

CD surgery, biologic treatment or new immunosuppressive drugs,throughout the study treatment period, are regarded as treatment failureand results in early treatment discontinuation.

5-ASA Compounds

The use of 5-ASA compounds are kept stable throughout the study.

Antibiotics

The use of antibiotics for the treatment of Crohn's disease is keptstable throughout the trial. Managing acute infections (not related toCrohn's disease) is allowed.

Corticosteroids

The dose of oral corticosteroids remains stable throughout the study:

-   1. Oral systemic corticosteroids—no more than prednisolone 2.5    mg/day (or equivalent) increase or decrease compared to baseline.-   2. Budesonide no change is permitted compared to baseline.-   3. IV or IM corticosteroid dose or corticosteroid enemas are not    allowed.

Immunosuppressives

Immunosuppressive treatment allowed by the protocol (AZA/6MP/MTX) iskept stable throughout the study. Addition of new immunosuppressive drugis not allowed

Other

-   1. Antidiarrehal drugs, analgesics, NSAIDs and topical preparations    are allowed (including topical dermatological, opthalmological or    inhale steroids).-   2. The use of probiotics is kept stable throughout the study.

Inclusion/Exclusion Criteria Inclusion Criteria

Subjects must meet all the inclusion criteria to be eligible:

-   1. Males and females 18-75 years old (inclusive).-   2. Subjects diagnosed with Crohn's disease for at least 3 months    prior to screening, which has been appropriately documented and    supported by endoscopy or radiology (performed within 36 months    prior to screening and after surgical resection), or surgery.-   3. Moderate to severe Crohn's disease patients as determined by a    CDAI score of 220-450 (inclusive).-   4. Subjects with C-Reactive Protein (CRP) levels above 5 mg/L at    screening or any time between screening to baseline, including at    baseline, OR documented endoscopic evidence of mucosal ulcerations    within 4 weeks prior to baseline.    -   a. Evidence of mucosal ulcerations is defined as the presence of        at least 2 ulcers 10 mm.    -   b. Documentation includes the endoscopy report with supporting        photo or video.-   5. Subjects willing and able to provide written, informed consent.

Exclusion Criteria

Any of the following excludes the subject from entering the study:

-   1. Subjects with a diagnosis of Indeterminate Colitis:-   2. Subjects with positive results on stool culture for enteric    pathogens (Salmonella, Shigella, Yersinia, Campylobacter or    Clostridia Difficile toxin assay), at screening.-   3. Subjects who have had bowel surgery within the 3 months prior to    screening or with planned elective surgery or hospitalization during    the course of the study (that may interfere with study compliance or    outcome).-   4. Subjects with clinically significant Short Bowel Syndrome.-   5. Subjects with clinically significant GI obstructive symptoms.-   6. Subjects with intra-abdominal abscess.-   7. Subjects with fistula with clinical or radiological evidence of    abscess.-   8. Subjects with ileostomy, colostomy or who receive parenteral    nutrition.-   9. Subjects with a clinically significant or unstable medical or    surgical condition that, in the Investigator's opinion, would    preclude safe and complete study participation, as determined by    medical history, physical examinations, ECG, laboratory testing or    imaging. Such conditions may include:    -   a. A cardiovascular or pulmonary disorder that cannot be        well-controlled by standard treatment permitted by the study        protocol.    -   b. Renal, metabolid or hematological diseases.    -   c. Any form of acute or chronic liver disease.    -   d. Known human immunodeficiency virus (HIV) positive status.    -   e. Systemic infection at screening.    -   f. A family history of Long-QT syndrome.    -   g. A history of drug and/or alcohol abuse.    -   h. A current major psychiatric disorder.-   10. Subjects with a ≧2× upper limit of normal (ULN) serum elevation    of either of the following at screening: ALT, AST, GGT, ALKP or    direct bilirubin.-   11. A QTc interval which is >500 msec (according to machine output),    obtained from:    -   a. Two ECG recordings at screening visit OR    -   b. The mean value calculated from 2 baseline ECG recordings.-   12. Subjects with history of any malignancy in the last year, prior    to screening, excluding basal cell carcinoma.-   13. Subjects treated with oral corticosteroids (e.g.    prednisolone/budesonide), who have initiated this treatment within    less than 4 weeks prior to screening.-   14. Subjects treated with more than 20 mg/day of prednisolone (or    equivalent) or budesonide >6 mg/day for CD at screening, or whose    corticosteroid dosage regimen is not stable for at least 2 weeks    prior to baseline. [stable dose defined as ≦2.5 mg prednisolone (or    equivalent) increase or decrease, no change in budesonide and no IV    or IM steroid administration, within the last 2 weeks prior to    baseline].-   15. Subjects treated with 5-ASA who are not on stable dose for at    least 2 weeks prior to screening.-   16. Subjects treated with antibiotics for CD who are not on a stable    dose for at least 2 weeks prior to screening.-   17. Subjects treated with 6-MP, AZA or MTX, who have initiated this    treatment within 12 weeks prior to screening or who are not on a    stable dose for at least 6 weeks prior to screening.-   18. Subjects treated with Anti-TNFs within 4 weeks prior to    screening [The percentage of subjects previously treated with    anti-TNF drugs are limited to approximately 60% of subjects    randomized for each cohort. All site principle investigators are    notified by the Sponsor when the quota of previous treatment with    anti-TNF drugs has been reached for each cohort].-   19. Subjects treated with cyclosporine, tacrolimus, mycophenolate    mofetil or thalidomide within 2 months prior to screening.-   20. Subjects treated with natalizumab within 6 months prior to    screening.-   21. Subjects who have used any other investigational drugs within 3    months prior to screening.-   22. Use of inhibitors of CYP3A4 within 2 weeks prior to base line    visit (1 month for fluoxetine).-   23. Use of amiodarone within 2 years prior to screening visit.-   24. Women who are pregnant or nursing at the time of screening, or    who intend to be during the study period.-   25. Women of child-bearing potential who do not practice an    acceptable method of birth control. Acceptable methods of birth    control in this study are: surgical sterilization, intrauterine    devices, oral contraceptive, contraceptive patch, long-acting    injectable contraceptive, partner's vasectomy, a double-protection    method (condom or diaphragm with spermicide).-   26. A known drug hypersensitivity that would preclude administration    of the study drug, such as hypersensitivity to: mannitol, meglumine    or sodium stearyl fumarate.-   27. Subjects unable to comply with the planned schedule of study    visits and study procedures.

Withdrawal Criteria/Treatment Failure

-   1. At the direction of the investigator, a subject who fails to    respond to the treatment protocol is withdrawn from the study.-   2. Rescue therapy for Crohn's disease (any new medication/treatment    or dose increase, not allowed by the protocol), throughout the study    treatment period, results in major protocol violation and is    regarded as a treatment failure.-   3. CD Surgery, biologic treatment of new immunosuppressive drugs,    throughout the study treatment period, is regarded as treatment    failure and results in early treatment discontinuation.

Monitoring Plan and Safety Stopping Rules

In any of the events listed below, the subject's participation in thestudy is discontinued immediately. The subject is followed untilresolution or stabilization of symptoms or lab abnormalities:

-   1. Any increase in ALT or AST to ≧3 times ULN, combined with either    ≧1.5 times ULN elevation of INR or ≧2 times ULN elevation of total    bilirubin.-   2. Any increase in ALT or AST to ≧3 times ULN, with the appearance    of worsening of fatigue, nausea, vomiting, right upper quadrant pain    or tenderness, fever, rash, or eosinophilia.-   3. Any increase in Alt or AST to levels ≧5 but <8 times ULN, which    is persistent for ≧2 weeks of repeated measurements.-   4. Any increase in ALT or AST to levels 8 times ULN.

Outcome Measures Clinical Effect

The study exploratory efficacy outcome measures are chosen according tothe draft EMEA guidelines for the treatment of active Crohn'sdisease/induction of remission (EMEA, 2007)

-   1. Proportion of subjects in clinical remission (total CDAI score    <150) at weeks 4, 6, 8 and 12.-   2. Proportion of subjects who respond to treatment (decrease from    baseline of at least 100 points in CDAI score ore remission) at week    4, 6, 8 and 12.-   3. Time to remission.-   4. Time to response.-   5. C-Reactive Protein (CRP) change from baseline at weeks 2, 4, 6, 8    and 12.-   6. Fecal calprotectin change from baseline to weeks 2, 4, 6, 8 and    12.-   7. Proportion of subjects with a decrease from baseline of at least    50% in the number of open draining fistulas.

Safety/Tolerability

-   1. Adverse events (AEs).-   2. Clinical laboratory values.-   3. Vital signs.-   4. ECG.-   5. Proportion of subjects who prematurely discontinue treatment.-   6. Proportion of subjects who prematurely discontinue treatment due    to AEs.-   7. Time to premature treatment discontinuation.-   8. Time to premature treatment discontinuation due to AEs.

Determination of the Highest Tolerable Dose

At any of the safety evaluations, the safety committee may determinethat a Dose Limiting Toxicity (DLT) has been reached. Criteria for DLTare not predefined and are based solely on the safety committee's bestmedical judgment.

The highest tolerable dose is defined as the dose level below the doseat which no further escalation is permitted, according to the decisionof the safety committee.

Pharmacokinetics/Population PK

Steady state parameters (AUC_(tau), C_(max), and C_(min)) are calculatedfor the 0.5 mg dose only (in a subset of sites)

The population approach is used to fit the plasma concentration-timedata from all dose groups, if possible. The effect of differentcovariates on the pharmacokinetics of laquinimod is evaluated in themodel (all sites, all cohorts).

Results

0.5 mg/day

0.5 mg/day oral dose of laquinimod in subjects with moderate to severeCrohn's disease (CDAI score of 220-450) reduces the symptoms of Crohn'sdisease in the subject, induces clinical response, induces and/ormaintains clinical remission, and/or inhibits disease progression and/ordisease complication in the subject. Specifically, the administration ofthe laquinimod reduces the subject's Crohn's Disease Activity Indexscore, lowers the subject's C-Reactive Protein level and/or fecalcalprotein level, and/or reduces the number of open draining fistulas inthe subject. Moreover, 0.5 mg/day oral dose of laquinimod in subjectswith moderate to severe Crohn's disease lowers the subject's dependenceon steroids.

1.0 mg/day

1.0 mg/day oral dose of laquinimod in subjects with moderate to severeCrohn's disease (CDAI score of 220-450) reduces the symptoms of Crohn'sdisease in the subject, induces clinical response, induces and/ormaintains clinical remission, and/or inhibits disease progression and/ordisease complication in the subject. Specifically, the administration ofthe laquinimod reduces the subject's Crohn's Disease Activity Indexscore, lowers the subject's C-Reactive Protein level and/or fecalcalprotein level, and/or reduces the number of open draining fistulas inthe subject. Moreover, 1.0 mg/day oral dose of laquinimod in subjectswith moderate to severe Crohn's disease lowers the subject's dependenceon steroids.

1.5 mg/day

1.5 mg/day oral dose of laquinimod in subjects with moderate to severeCrohn's disease (CDAI score of 220-450) reduces the symptoms of Crohn'sdisease in the subject, induces clinical response, induces and/ormaintains clinical remission, and/or inhibits disease progression and/ordisease complication in the subject. Specifically, the administration ofthe laquinimod reduces the subject's Crohn's Disease Activity Indexscore, lowers the subject's C-Reactive Protein level and/or fecalcalprotein level, and/or reduces the number of open draining fistulas inthe subject. Moreover, 1.5 mg/day oral dose of laquinimod in subjectswith moderate to severe Crohn's disease lowers the subject's dependenceon steroids.

2.0 mg/day

2.0 mg/day oral dose of laquinimod in subjects with moderate to severeCrohn's disease (CDAI score of 220-450) reduces the symptoms of Crohn'sdisease in the subject, induces clinical response, induces and/ormaintains clinical remission, and/or inhibits disease progression and/ordisease complication in the subject. Specifically, the administration ofthe laquinimod reduces the subject's Crohn's Disease Activity Indexscore, lowers the subject's C-Reactive Protein level and/or fecalcalprotein level, and/or reduces the number of open draining fistulas inthe subject. Moreover, 2.0 mg/day oral dose of laquinimod in subjectswith moderate to severe Crohn's disease lowers the subject's dependenceon steroids.

REFERENCES

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Infliximab therapy in Crohn's    disease: safety issues. Neth J Med 2003; 61:100-104.-   17. Jonsson S, Andersson G, Fex T, Fristedt T, Hedlund G, Jansson K,    Abramo L, Fritzson I, Pekarski O, Runstrom A, Sandin H, Thuvesson I,    Bjork A. Synthesis and biological evaluation of new    1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for treatment of    autoimmune disorders: structure-activity relationship. J Med Chem.    2004 Apr. 8; 47(8):2075-88.-   18. Kasper D L, Braunwald E, Fauci A S, Hauser S L, Longo D L,    Jameson J L, Loscalzo J. (2008). Harrison's principles of internal    medicine (17th ed.). New York: McGraw-Hill Medical Publishing    Division. ISBN 978-0-07-146633-9.-   19. Kozuch P L, Hanauer S B. Treatment of inflammatory bowel    disease: A review of medical therapy. World J Gastroenterol; 2008;    14(3):354-377.-   20. Laquinimod Investigator's Brochure (IB), Ed. 4, November 2007.    Addendum No. 1. 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What is claimed is:
 1. A method of treating a subject suffering fromCrohn's disease, the method comprising periodically administering to thesubject an amount of laquinimod or pharmaceutically acceptable saltthereof effective to treat the subject.
 2. The method of claim 1,wherein the amount of laquinimod is effective to reduce a symptom ofCrohn's disease in the subject, induce clinical response, induce ormaintain clinical remission, inhibit disease progression, or inhibit adisease complication in the subject.
 3. The method of claim 1, whereinthe amount of laquinimod is effective to reduce the Crohn's DiseaseActivity Index score of the subject, lower the C-Reactive Protein levelof the subject, lower the fecal calprotein level of the subject, orreduce the number of open draining fistulas in the subject.
 4. Themethod of claim 3, wherein the Crohn's Disease Activity Index score ofthe subject is reduced by at least 100 points.
 5. The method of claim 3or 4, wherein the Crohn's Disease Activity Index score of the subject isreduced to under
 150. 6. The method of any one of claims 3-5, whereinthe number of open draining fistulas in the subject is decreased atleast 50% as compared to prior to initiation of the periodicadministration.
 7. The method of any one of claims 1-6, wherein theperiodic administration is oral.
 8. The method of any one of claims 1-7,wherein the amount is administered by a unit dose of 0.5 mg oflaquinimod.
 9. The method of any one of claims 1-8, wherein the periodicadministration is daily administration.
 10. The method of claim 9,wherein the amount of laquinimod is 0.5-2.0 mg/day.
 11. The method ofclaim 10, wherein the amount of laquinimod is 1.0 mg/day.
 12. The methodof claim 10, wherein the amount of laquinimod is 1.5 mg/day.
 13. Themethod of claim 10, wherein the amount of laquinimod is 2.0 mg/day. 14.The method of any one of claims 1-13, wherein a loading dose of anamount different from the intended dose is administered for a period oftime at the start of the periodic administration.
 15. The method ofclaim 14, wherein the loading dose is double the amount of the intendeddose.
 16. The method of claim 14 or 15, wherein the loading isadministered for two days at the start of the periodic administration.17. The method of any one of claims 1-16, wherein the subject had activemoderate to severe Crohn's disease prior to the administration oflaquinimod.
 18. The method of any one of claims 1-17, wherein thesubject had a Crohn's Disease Activity Index score of 220-450 prior tothe administration of laquinimod.
 19. The method of any one of claims1-18, wherein the subject had a C-Reactive Protein level of above 5 mg/Lprior to the administration of laquinimod.
 20. The method of any one ofclaims 17-19, wherein diagnosis of the subject prior to administrationexcluded Indeterminate Colitis.
 21. The method of any one of claims17-19, wherein diagnosis of the subject prior to administration excludedUlcerative Colitis.
 22. The method of any one of claims 1-21, whereinthe periodic administration continues for 8 weeks or more.
 23. Themethod of any one of claims 1-22, wherein the laquinimod is in the formof laquinimod sodium.
 24. The method of any one of claims 1-23, whereinthe subject is a human.
 25. The method of any one of claims 1-24,further comprising administration of 5-aminosalicylic acid, antibiotics,corticosteroids, immunosuppressors, TNFα agents or anti-integrins. 26.Use of laquinimod in the manufacture of a medicament for treating asubject suffering from Crohn's disease.
 27. A pharmaceutical compositioncomprising laquinimod for use in treating a subject suffering fromCrohn's disease.